1. Field of the Invention
The invention relates to microcapsules, methods for making microcapsules, encapsulating pharmaceutical compounds in microcapsules, microcapsule encapsulated pharmaceutical compositions and products, and methods of using these compositions. The invention also relates to controlled delivery of a substance contained in a microcapsule through the use of magnetic particles that are heated upon exposure to an electromagnetic field.
2. Description of the Related Art
Although encapsulation of a drug in a microcapsule or other carrier addresses several problems of drug delivery, an area of interest in the art of drug delivery is still the specific, controlled release of the drug from the microcapsule when it reaches the target site. Several approaches have been described to solve this problem, including heating liposomes to the melting temperature of the phospholipid bilayer by inducing local hyperthermia or by heating magnetic powders incorporated into the membranes, and also including physically shaking microcapsules by ultrasound or by oscillating magnetic fields. However, the inventors are aware of no previous method in which a permanent hole is melted in a microcapsule comprising a polymer outer shell, so that the contents are released through the pore.
In a controlled delivery system described by Supersaxo et al. in U.S. Pat. No. 5,470,582, microparticles are made from polymers such as polyesters, polyamides, polyanhydrides and polyacrylates with pre-formed pores and an active agent is allowed to migrate into the microparticles through the pores. After administration, the active agent is released through the pores by diffusion. A burst of release may be caused by application of ultrasonic radiation. Another system, described by Mathiowitz et al. in U.S. Pat. No. 4,898,734, is also based on passive or facilitated diffusion of an active agent from pore-containing polymer microspheres. Methods of facilitating diffusion include exposure to high temperature, light, or ultrasound. This patent also describes degradable microspheres and microspheres immobilized in a polymer matrix. A controlled release delivery system described by Modi in U.S. Pat. No. 5,417,982 is biodegradable copolymer based microspheres in which delayed release of an active agent is controlled by the time required for enzymatic digestion of the polymer matrix. Wheatley et al., in U.S. Pat. No. 4,933,185, describe microcapsules having an inner core and an outer, ionic skin. An active agent and an enzyme are encapsulated in the inner core, such that the enzyme degrades the inner core and releases the active agent.
Controlled release of drugs from liposomes has been achieved by using temperature sensitive polymers in the formation of the liposomes (Magin et al. 1986). Once the liposomes are localized in the target tissue (or tumor) the drug can be rapidly released if the local tissue temperature can be raised above the transition temperature of the liposome membrane. This requires some method of controlled tissue heating which is difficult to achieve without complicated surgical procedures, implanted interstitial antennas or ultrasonics to produce effective local hyperthermia (Hand, 1991). Thermosensitive liposomes have been prepared from a variety of natural and synthetic lipids such as dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, and cholesterol to have transition temperatures of 41-43° C. so that the outer phospholipid membrane melts and releases contained drugs in response to local hyperthermia. Attempts have been made to use these liposomes and local tissue hyperthermia for achieving drug targeting to tumors.
Chelvi and Rathan (1995) prepared temperature-sensitive liposomes from natural lipids, egg phosphatidylcholine:cholesterol (PC:Ch) in a 7:1 molar ratio and ethanol, 6% (v/v) having a transition temperature of 43° C. Fluorescence labeled calcein was encapsulated in the liposomes and administered to mice, a group of whose tumor-bearing legs were immersed in a water bath to achieve a tumor temperature of 43° C. and held there for one hour. Fluorescence microscopy demonstrated the release of calcein from the temperature sensitive liposomes. The in vivo efficacy of temperature-sensitive unilamellar vesicles containing dacarbazine in combination with hyperthermia was detected in murine fibrosarcomas.
Kakinuma et al. (1995) also used thermosensitive liposomes containing cis-diaminedichloroplatin (CDDP) to deliver cytotoxic doses to brain tumors by dissolving the liposomes with localized brain heating. The investigators studied the anti-tumor effect on rat malignant glioma. Ten days after tumor inoculation, the rats were assigned to one of six treatment groups: control, free CDDP, hyperthermia, free CDDP+hyperthermia, liposomes containing CDDP (CDDP-liposomes), and CDDP-liposomes+hyperthermia. Liposomes containing CDDP or free CDDP were injected via the tail vein. Brain tumor heating was administered by means of a radiofrequency antenna designed for rat brain. The rats treated with CDDP-liposome+hyperthermia had the longest survival time and the tumor CDDP level of this group was the highest when compared to the other groups. Histophathological examination showed that tumor cells were necrotized but surrounding normal brain tissue remained undamaged. The greater anti-tumor effects suggested that the combination of thermosensitive liposome and localized hyperthermia better focused anti-tumor drugs to the tumor.
Thermosensitive liposomes designed for drug release by hyperthermia have been tested at different local tissue temperatures (Kakinuma et al., 1996). Four groups were studied: the first received free Cisplatin (cis-diaminedichloroplatin, CDDP); the second received free CDDP and above 41° C. local brain heating for 30 minutes; the third group received liposomes containing CDDP (CDDP-liposomes); and the fourth group received CDDP-liposome and above 41° C. local brain heating for 30 minutes. Brain CDDP levels were significantly higher in group 4, while those in the other groups were undetectable. The present inventors have also studied the distribution of Evans blue dye (Eb) in the artificially heated region of dogs' brain. One group received free Eb and the other group received liposomes containing Eb (Eb-liposome). While the extravasation of free Eb was localized in regions heated to greater than 44° C., that of Eb-liposome was extended up to the regions heated at 41° C. It appears that the use of thermosensitive liposomes and hyperthermia not only contributes to the brain tumor killing as direct thermal killing does, but also helps to increase the concentration of chemotherapeutic drugs into the tumor invaded zones with mild local hyperthermia of only 41° C.
A method of localizing a drug carrier that has been described is the inclusion of magnetic particles in the carrier. The encapsulation of oil-suspended magnetic particles into microcapsules with hydrophilic, organic colloidal membranes is described in U.S. Pat. No. 2,971,916. The magnetic particles were used to direct the microcapsules to a magnetized location on a paper medium, where the capsules were crushed to deliver an ink or stain to the paper.
Microspheres for intravascular administration comprising magnetic particles in a biodegradable carrier are described in U.S. Pat. Nos. 4,247,406 and 4,345,588. The microcapsules described in these patents comprise magnetic particles embedded in a polyamino acid matrix, such as albumin, which also acts as a carrier for a therapeutic drug. The microcapsules are infused into an artery that feeds a particular capillary bed and are then immobilized by the application of a magnetic field across the capillary bed. The microcapsules are held in the bed by the magnetic field until the polymer matrix is dissolved by proteolytic enzymes, or they may be drawn into the surrounding tissues by application of a stronger field. As described in these patents, when these carriers are drawn into tissue in order to directly deliver the drugs, they become immobilized in the tissue where they remain after the field is terminated.
Liposomes encapsulating magnetic particles are described by Chang in U.S. Pat. No. 4,652,257. These liposomes are also used to localize a chemotherapeutic drug in a capillary bed by application of a magnetic field. After the liposomes are immobilized at the target site, the magnetic particles are vibrated by application of an oscillating magnetic field. The particles are vibrated in order to destabilize, or to rupture the lipid membrane, thus releasing the drug. The liposomes described by Chang are small (on the order of 1-2 micrometers with ferromagnetic particles of about 100 to 1000 angstroms), and are further limited in that only hydrophilic drugs can be delivered from the liposomes. The small size of these liposomes limits their utility because the size and shape is a factor in the distribution and drug delivery of the liposomes in the tissues. Additionally, in the liposomes described by Chang, it is the mechanical force of the vibrating ferromagnetic particles that destabilizes or ruptures the membrane, rather than any local heating effect.
It is evident, therefore, that improvements are still needed to address certain drawbacks of conventional liposome or microcapsule delivery systems. Delivery of a variety of active drugs to a specific site in the body with a liposome formulation still presents difficulties, for example. There is a need for a system that would address certain disadvantages of thermosensitive liposomes for drug delivery. These delivery systems are primarily useful for drugs that diffuse out of the carrier across the outer phospholipid bi-layer membrane, or in liposomes that are phagocytized by a particular cell type. Thermosensitive liposomes may be melted by local hyperthermia, but unfortunately, methods for creating hyperthermia in local tissues are not precise and are largely dependent on the local tissue composition. Heating may also be counteracted by blood flow cooling. Thermosensitive liposomes (or microcapsules) are limited to those having outer membranes that can be melted at temperatures below those that cause permanent damage to healthy tissues, usually a maximum of 41-44° C. In those methods in which heating or mechanical forces are used to disrupt or melt the liposome membrane, or even melt a hole in the membrane, the phospholipid bilayer will rapidly extend to close off the hole and thereby re-form the lipid bilayer. There is a need, therefore for a method of controlled delivery of a drug at the tumor site without depending on passive diffusion, local hyperthermia of tissues, or temporary phase changes in the outer membrane.